Graft versus host disease

Section editor
	Talal Hilal, MD Mayo Clinic Phoenix, AZ, USA

9 regimens on this page 16 variants on this page

Note: most of these regimens include complex dose adjustments based on therapeutic troughs, concomitant medications, and other factors. Therefore, the focus on this page will be inclusion of drug names and references, but not necessarily drug dosages.

• We have moved How I Treat articles to a dedicated page.

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASBMT

• 2012: Martin et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation PubMed

EBMT/ELN

• 2013: Ruutu et al. Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice PubMed

ESBMT

• 2024: Penack et al. Prophylaxis and management of graft-versus-host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation PubMed
  • 2020: Penack et al. Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation PubMed

Prevention

This is very basic for now, to expand in the future. Information can also be found under individual regimens on the allogeneic HSCT page.

ATG (Rabbit) monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kröger et al. 2016 (ATGFamilyStudy)	2006-12 to 2012-02	Phase 3 (E-esc)	No ATG	Superior cGVHD rate (primary endpoint)

Immunosuppressive therapy

• Antithymocyte globulin, rabbit ATG (Thymoglobulin) 10 mg/kg IV once per day on days -3 to -1

One course

References

1. CBMTG 0801: Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, Gallagher G, Kerr H, Kuruvilla J, Lee SJ, Moore J, Nevill T, Popradi G, Roy J, Schultz KR, Szwajcer D, Toze C, Foley R; Canadian Blood and Marrow Transplant Group. Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial. Lancet Oncol. 2016 Feb;17(2):164-173. Epub 2015 Dec 24. link to original article PubMed NCT01217723
2. ATGFamilyStudy: Kröger N, Solano C, Wolschke C, Bandini G, Patriarca F, Pini M, Nagler A, Selleri C, Risitano A, Messina G, Bethge W, Pérez de Oteiza J, Duarte R, Carella AM, Cimminiello M, Guidi S, Finke J, Mordini N, Ferra C, Sierra J, Russo D, Petrini M, Milone G, Benedetti F, Heinzelmann M, Pastore D, Jurado M, Terruzzi E, Narni F, Völp A, Ayuk F, Ruutu T, Bonifazi F. Antilymphocyte globulin for prevention of chronic graft-versus-host disease. N Engl J Med. 2016 Jan 7;374(1):43-53. link to original article contains dosing details in manuscript PubMed NCT00678275
3. ProfGVHD1: Locatelli F, Bernardo ME, Bertaina A, Rognoni C, Comoli P, Rovelli A, Pession A, Fagioli F, Favre C, Lanino E, Giorgiani G, Merli P, Pagliara D, Prete A, Zecca M. Efficacy of two different doses of rabbit anti-T-lymphocyte globulin to prevent graft-versus-host disease in children with haematological malignancies transplanted from an unrelated donor: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Aug;18(8):1126-1136. Epub 2017 Jul 10. link to original article PubMed NCT00934557

Cyclophosphamide, Mycophenolate mofetil, Tacrolimus

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Luznik et al. 2008 (J9966)	1999-2006	Non-randomized
Luznik et al. 2008 (FHCRC 1667)	1999-2006	Non-randomized
Solomon et al. 2012	2009-01 to 2011-03	Phase 2
Bolaños-Meade et al. 2023 (BMT CTN 1703)	2019-06-25 to 2021-06-18	Phase 3 (E-esc)	MTX & Tacrolimus	Superior GVHD-free RFS (primary endpoint) GVHD-free RFS12: 52.7% vs 34.9% (HR 0.64, 95% CI 0.49-0.83)

Immunosuppressive therapy

• Cyclophosphamide (Cytoxan)
• Mycophenolate mofetil (CellCept)
• Tacrolimus (Prograf)

References

1. J9966: Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, Gooley TA, Piantadosi S, Kaup M, Ambinder RF, Huff CA, Matsui W, Bolaños-Meade J, Borrello I, Powell JD, Harrington E, Warnock S, Flowers M, Brodsky RA, Sandmaier BM, Storb RF, Jones RJ, Fuchs EJ. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008 Jun;14(6):641-50. link to original article link to PMC article PubMed NCT00006042
2. FHCRC 1667: Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, Gooley TA, Piantadosi S, Kaup M, Ambinder RF, Huff CA, Matsui W, Bolaños-Meade J, Borrello I, Powell JD, Harrington E, Warnock S, Flowers M, Brodsky RA, Sandmaier BM, Storb RF, Jones RJ, Fuchs EJ. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008 Jun;14(6):641-50. link to original article link to PMC article PubMed
3. Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK, Morris LE, Bashey A. Haploidentical transplantation using T cell replete peripheral blood stem cells and myeloablative conditioning in patients with high-risk hematologic malignancies who lack conventional donors is well tolerated and produces excellent relapse-free survival: results of a prospective phase II trial. Biol Blood Marrow Transplant. 2012 Dec;18(12):1859-66. Epub 2012 Aug 1. link to original article PubMed
4. BMT CTN 1703: Bolaños-Meade J, Hamadani M, Wu J, Al Malki MM, Martens MJ, Runaas L, Elmariah H, Rezvani AR, Gooptu M, Larkin KT, Shaffer BC, El Jurdi N, Loren AW, Solh M, Hall AC, Alousi AM, Jamy OH, Perales MA, Yao JM, Applegate K, Bhatt AS, Kean LS, Efebera YA, Reshef R, Clark W, DiFronzo NL, Leifer E, Horowitz MM, Jones RJ, Holtan SG; BMT CTN 1703 Investigators. Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis. N Engl J Med. 2023 Jun 22;388(25):2338-2348. link to original article PubMed NCT03959241

Cyclophosphamide & Cyclosporine

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Broers et al. 2022 (HOVON-96)	2013-2018	Phase 3 (E-switch-ic)	CsA & MPA	Superior GRFS (primary endpoint)

Immunosuppressive therapy

• Cyclophosphamide (Cytoxan)
• Cyclosporine

References

1. HOVON-96: Broers AEC, de Jong CN, Bakunina K, Hazenberg MD, van Marwijk Kooy M, de Groot MR, van Gelder M, Kuball J, van der Holt B, Meijer E, Cornelissen JJ. Posttransplant cyclophosphamide for prevention of graft-versus-host disease: results of the prospective randomized HOVON-96 trial. Blood Adv. 2022 Jun 14;6(11):3378-3385. link to original article link to PMC article PubMed NL2128

Cyclosporine & Methotrexate

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Ratanatharathorn et al. 1998	1993-05 to 1994-11	Phase 3 (C)	Methotrexate & Tacrolimus	Inferior aGVHD rate
Finke et al. 2009 (AP-AS-21-DE)	2003-05-26 to 2007-02-08	Phase 3 (C)	Cyclosporine, MTX, ATG	Did not meet primary endpoint of severe aGVHD or death within 100 days of transplantation	Similar NRM
Kennedy et al. 2021	2014-07 to 2017-09	Phase 3 (C)	Cyclosporine, MTX, Tocilizumab	Did not meet primary endpoint	Similar NRM

Note: while AP-AS-21-DE did not meet its primary endpoint, there was a clear finding of superior control of cGVHD in the experimental arm.

Immunosuppressive therapy

• Cyclosporine 3 mg/kg/day IV continuous infusion, started on day -1
• Methotrexate (MTX) 15 mg/m² IV once on day +1, then 10 mg/m² IV once per day on days +3, +6, +11

One course

References

1. Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D, Fay JW, Nademanee A, Antin JH, Christiansen NP, van der Jagt R, Herzig RH, Litzow MR, Wolff SN, Longo WL, Petersen FB, Karanes C, Avalos B, Storb R, Buell DN, Maher RM, Fitzsimmons WE, Wingard JR. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998 Oct 1;92(7):2303-14. link to original article contains dosing details in manuscript PubMed
2. Ruutu T, Volin L, Parkkali T, Juvonen E, Elonen E. Cyclosporine, methotrexate, and methylprednisolone compared with cyclosporine and methotrexate for the prevention of graft-versus-host disease in bone marrow transplantation from HLA-identical sibling donor: a prospective randomized study. Blood. 2000 Oct 1;96(7):2391-8. link to original article contains dosing details in manuscript PubMed
   1. Update: Ruutu T, Nihtinen A, Niittyvuopio R, Juvonen E, Volin L. A randomized study of cyclosporine and methotrexate with or without methylprednisolone for the prevention of graft-versus-host disease: Improved long-term survival with triple prophylaxis. Cancer. 2018 Feb 15;124(4):727-733. Epub 2017 Nov 7. link to original article PubMed
3. AP-AS-21-DE: Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, Volin L, Ruutu T, Heim DA, Schwerdtfeger R, Kolbe K, Mayer J, Maertens JA, Linkesch W, Holler E, Koza V, Bornhäuser M, Einsele H, Kolb HJ, Bertz H, Egger M, Grishina O, Socié G; ATG-Fresenius Trial Group. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009 Sep;10(9):855-64. Epub 2009 Aug 18. link to original article PubMed NCT00655343
   1. Update: Socié G, Schmoor C, Bethge WA, Ottinger HD, Stelljes M, Zander AR, Volin L, Ruutu T, Heim DA, Schwerdtfeger R, Kolbe K, Mayer J, Maertens JA, Linkesch W, Holler E, Koza V, Bornhäuser M, Einsele H, Kolb HJ, Bertz H, Egger M, Grishina O, Finke J; ATG-Fresenius Trial Group. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood. 2011 Jun 9;117(23):6375-82. Epub 2011 Apr 5. link to original article PubMed
   2. Update: Finke J, Schmoor C, Bethge WA, Ottinger H, Stelljes M, Volin L, Heim D, Bertz H, Grishina O, Socie G. Long-term outcomes after standard graft-versus-host disease prophylaxis with or without anti-human-T-lymphocyte immunoglobulin in haemopoietic cell transplantation from matched unrelated donors: final results of a randomised controlled trial. Lancet Haematol. 2017 Jun;4(6):e293-e301. link to original article PubMed
4. Kennedy GA, Tey SK, Buizen L, Varelias A, Gartlan KH, Curley C, Olver SD, Chang K, Butler JP, Misra A, Subramoniapillai E, Morton AJ, Durrant S, Henden AS, Moore J, Ritchie D, Gottlieb D, Cooney J, Paul SK, Hill GR. A phase 3 double-blind study of the addition of tocilizumab vs placebo to cyclosporin/methotrexate GVHD prophylaxis. Blood. 2021 Apr 8;137(14):1970-1979. link to original article PubMed ACTRN12614000266662

Cyclosporine, Methotrexate, ATG

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Finke et al. 2009 (AP-AS-21-DE)	2003-05-26 to 2007-02-08	Phase 3 (E-esc)	Cyclosporine & MTX	Did not meet primary endpoint of severe aGVHD or death within 100 days of transplantation	Similar NRM
Walker et al. 2020 (CBMTG 0801)	2010-06-09 to 2013-07-08	Phase 3 (E-esc)	Cyclosporine & MTX	Seems to have superior OS (secondary endpoint)	Similar NRM

Note: while AP-AS-21-DE did not meet its primary endpoint, there was a clear finding of superior control of cGVHD in the experimental arm.

Immunosuppressive therapy

• Cyclosporine
• Methotrexate (MTX)
• Antithymocyte globulin, rabbit ATG (ATG-Fresenius)

References

1. AP-AS-21-DE: Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, Volin L, Ruutu T, Heim DA, Schwerdtfeger R, Kolbe K, Mayer J, Maertens JA, Linkesch W, Holler E, Koza V, Bornhäuser M, Einsele H, Kolb HJ, Bertz H, Egger M, Grishina O, Socié G; ATG-Fresenius Trial Group. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009 Sep;10(9):855-64. Epub 2009 Aug 18. link to original article PubMed NCT00655343
   1. Update: Socié G, Schmoor C, Bethge WA, Ottinger HD, Stelljes M, Zander AR, Volin L, Ruutu T, Heim DA, Schwerdtfeger R, Kolbe K, Mayer J, Maertens JA, Linkesch W, Holler E, Koza V, Bornhäuser M, Einsele H, Kolb HJ, Bertz H, Egger M, Grishina O, Finke J; ATG-Fresenius Trial Group. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood. 2011 Jun 9;117(23):6375-82. Epub 2011 Apr 5. link to original article PubMed
   2. Update: Finke J, Schmoor C, Bethge WA, Ottinger H, Stelljes M, Volin L, Heim D, Bertz H, Grishina O, Socie G. Long-term outcomes after standard graft-versus-host disease prophylaxis with or without anti-human-T-lymphocyte immunoglobulin in haemopoietic cell transplantation from matched unrelated donors: final results of a randomised controlled trial. Lancet Haematol. 2017 Jun;4(6):e293-e301. link to original article PubMed
2. CBMTG 0801: Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, Gallagher G, Kerr H, Kuruvilla J, Lee SJ, Moore J, Nevill T, Popradi G, Roy J, Schultz KR, Szwajcer D, Toze C, Foley R; Cell Therapy Transplant Canada. Addition of anti-thymocyte globulin to standard graft-versus-host disease prophylaxis versus standard treatment alone in patients with haematological malignancies undergoing transplantation from unrelated donors: final analysis of a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2020 Feb;7(2):e100-e111. Epub 2020 Jan 17. link to original article PubMed NCT01217723

Cyclosporine, Methotrexate, Methylprednisolone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ruutu et al. 2000	1989-1994	Phase 3 (E-esc)	Cyclosporine & MTX	Lower rate of aGVHD

Immunosuppressive therapy

• Cyclosporine 3 mg/kg/day IV continuous infusion over 15 days, started on day -1, then 1.5 mg/kg PO twice per day on days +16 to +365, then tapered off over the next 6 weeks
• Methotrexate (MTX) 15 mg/m² IV once on day +1, then 10 mg/m² IV once per day on days +3, +6, +11
• Methylprednisolone (Solumedrol) 0.25 mg/kg PO twice per day on days +14 to +20, then 0.5 mg/kg PO twice per day on days +21 to +34, then 0.25 mg/kg PO twice per day on days +35 to +48, then 0.125 mg/kg PO twice per day on days +49 to +69, then 0.12 mg/kg PO once per day on days +70 to +89, then 0.12 mg/kg PO once every other day on days +90, +92, +94, +96, +98, then 0.06 mg/kg PO once every other day on days +100, +102, +104, +106, +108, +110

Supportive therapy

• Leucovorin (Folinic acid) 15 mg/m² IV once on day +1, then 10 mg/m² IV once per day on days +3, +6, +11, given 6 hours after each dose of MTX

One course

Dose and schedule modifications

• Cyclosporine dose was modified to maintain levels less than 200 mcg/L

References

1. Ruutu T, Volin L, Parkkali T, Juvonen E, Elonen E. Cyclosporine, methotrexate, and methylprednisolone compared with cyclosporine and methotrexate for the prevention of graft-versus-host disease in bone marrow transplantation from HLA-identical sibling donor: a prospective randomized study. Blood. 2000 Oct 1;96(7):2391-8. link to original article contains dosing details in manuscript PubMed
   1. Update: Ruutu T, Nihtinen A, Niittyvuopio R, Juvonen E, Volin L. A randomized study of cyclosporine and methotrexate with or without methylprednisolone for the prevention of graft-versus-host disease: Improved long-term survival with triple prophylaxis. Cancer. 2018 Feb 15;124(4):727-733. Epub 2017 Nov 7. link to original article PubMed

Cyclosporine, Methotrexate, Prednisone

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Chao et al. 1993	Phase 3 (E-esc)	Cyclosporine & Prednisone	Seems to have lower rate of grade II to IV aGVHD

Immunosuppressive therapy

• Cyclosporine
• Methotrexate (MTX)
• Prednisone (Sterapred)

References

1. Chao NJ, Schmidt GM, Niland JC, Amylon MD, Dagis AC, Long GD, Nademanee AP, Negrin RS, O'Donnell MR, Parker PM, Smith EP, Snyder DS, Stein AS, Wong RM, Blume KG, Forman SJ. Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prophylaxis of acute graft-versus-host disease. N Engl J Med. 1993 Oct 21;329(17):1225-30. link to original article PubMed

Cyclosporine & Mycophenolate mofetil

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Sandmaier et al. 2019 (FH 2448.00)	Phase 3 (C)	Cyclosporine, MMF, Sirolimus	Higher rate of grade II to IV aGVHD at d+100

Immunosuppressive therapy

• Cyclosporine 5 mg/kg PO twice per day from day -3 to day +96, then tapered off by day +150 in the absence of GVHD
• Mycophenolate mofetil (CellCept) 15 mg/kg PO three times per day from day 0 to day +30, then 15 mg/kg PO twice per day from day +31 to day +150, then tapered off by day +180 in the absence of GVHD

References

1. FH 2448.00: Sandmaier BM, Kornblit B, Storer BE, Olesen G, Maris MB, Langston AA, Gutman JA, Petersen SL, Chauncey TR, Bethge WA, Pulsipher MA, Woolfrey AE, Mielcarek M, Martin PJ, Appelbaum FR, Flowers MED, Maloney DG, Storb R. Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial. Lancet Haematol. 2019 Aug;6(8):e409-e418. Epub 2019 Jun 24. link to original article contains dosing details in abstract link to PMC article PubMed NCT01231412

Cyclosporine, Mycophenolate mofetil, Sirolimus

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Sandmaier et al. 2019 (FH 2448.00)	Phase 3 (E-esc)	Cyclosporine & MMF	Lower rate of grade II to IV aGVHD at d+100 (primary endpoint)

Immunosuppressive therapy

• Cyclosporine 5 mg/kg PO twice per day from day -3 to day +96, then tapered off by day +150 in the absence of GVHD
• Mycophenolate mofetil (CellCept) 15 mg/kg PO three times per day from day 0 to day +30, then 15 mg/kg PO twice per day from day +31 to day +150, then tapered off by day +180 in the absence of GVHD
• Sirolimus (Rapamune) 2 mg PO once per day from day -3 to day +150 (adjusted to maintain trough level of 3 to 12 ng/mL), then tapered off by day +180 in the absence of GVHD

References

1. FH 2448.00: Sandmaier BM, Kornblit B, Storer BE, Olesen G, Maris MB, Langston AA, Gutman JA, Petersen SL, Chauncey TR, Bethge WA, Pulsipher MA, Woolfrey AE, Mielcarek M, Martin PJ, Appelbaum FR, Flowers MED, Maloney DG, Storb R. Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial. Lancet Haematol. 2019 Aug;6(8):e409-e418. Epub 2019 Jun 24. link to original article contains dosing details in abstract link to PMC article PubMed NCT01231412

Methotrexate & Tacrolimus

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ratanatharathorn et al. 1998	1993-05 to 1994-11	Phase 3 (E-switch-ic)	Cyclosporine & Methotrexate	Superior aGVHD rate
Cutler et al. 2014 (BMT CTN 0402)	2006-11 to 2011-10	Phase 3 (C)	Sirolimus & Tacrolimus	Did not meet primary endpoint of day +114 grade 2-4 aGVHD
Pulsipher et al. 2014 (COG ASCT0431)	2007-03 to 2011-05	Phase 3 (C)	Methotrexate, Sirolimus, Tacrolimus	Did not meet primary endpoint of EFS24
Luznik et al. 2021 (BMT CTN 1301)	2015-09 to 2018-06	Phase 3 (C)	1. PTCy 2. CD34 selected T-cell–depleted PBSC graft without additional immunosuppression	Did not meet co-primary endpoint of CRFS
Bolaños-Meade et al. 2023 (BMT CTN 1703)	2019-06-25 to 2021-06-18	Phase 3 (C)	Cyclophosphamide, Mycophenolate mofetil, Tacrolimus	Inferior GVHD-free RFS

Immunosuppressive therapy

• Methotrexate (MTX) 15 mg/m² IV once on day +1, then 10 mg/m² IV once per day on days +3, +6, +11
• Tacrolimus (Prograf) starting on day -3 until at least day +90
  • Goal trough level of 5 to 15 ng/mL

One course

References

1. Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D, Fay JW, Nademanee A, Antin JH, Christiansen NP, van der Jagt R, Herzig RH, Litzow MR, Wolff SN, Longo WL, Petersen FB, Karanes C, Avalos B, Storb R, Buell DN, Maher RM, Fitzsimmons WE, Wingard JR. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998 Oct 1;92(7):2303-14. link to original article PubMed
2. COG ASCT0431: Pulsipher MA, Langholz B, Wall DA, Schultz KR, Bunin N, Carroll WL, Raetz E, Gardner S, Gastier-Foster JM, Howrie D, Goyal RK, Douglas JG, Borowitz M, Barnes Y, Teachey DT, Taylor C, Grupp SA. The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children's Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial. Blood. 2014 Mar 27;123(13):2017-25. Epub 2014 Feb 4. link to original article link to PMC article PubMed NCT00382109
3. BMT CTN 0402: Cutler C, Logan B, Nakamura R, Johnston L, Choi S, Porter D, Hogan WJ, Pasquini M, MacMillan ML, Hsu JW, Waller EK, Grupp S, McCarthy P, Wu J, Hu ZH, Carter SL, Horowitz MM, Antin JH. Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood. 2014 Aug 21;124(8):1372-7. Epub 2014 Jun 30. link to original article link to PMC article PubMed NCT00406393
4. BMT CTN 1301: Luznik L, Pasquini MC, Logan B, Soiffer RJ, Wu J, Devine SM, Geller N, Giralt S, Heslop HE, Horowitz MM, Jones RJ, Litzow MR, Mendizabal A, Muffly L, Nemecek ER, O'Donnell L, O'Reilly RJ, Palencia R, Schetelig J, Shune L, Solomon SR, Vasu S, Ho VT, Perales MA. Randomized Phase III BMT CTN Trial of Calcineurin Inhibitor-Free Chronic Graft-Versus-Host Disease Interventions in Myeloablative Hematopoietic Cell Transplantation for Hematologic Malignancies. J Clin Oncol. 2022 Feb 1;40(4):356-368. Epub 2021 Dec 2. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02345850
5. BMT CTN 1703: Bolaños-Meade J, Hamadani M, Wu J, Al Malki MM, Martens MJ, Runaas L, Elmariah H, Rezvani AR, Gooptu M, Larkin KT, Shaffer BC, El Jurdi N, Loren AW, Solh M, Hall AC, Alousi AM, Jamy OH, Perales MA, Yao JM, Applegate K, Bhatt AS, Kean LS, Efebera YA, Reshef R, Clark W, DiFronzo NL, Leifer E, Horowitz MM, Jones RJ, Holtan SG; BMT CTN 1703 Investigators. Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis. N Engl J Med. 2023 Jun 22;388(25):2338-2348. link to original article PubMed NCT03959241

Methotrexate, Tacrolimus, Tocilizumab

Regimen

Study	Dates of enrollment	Evidence
Drobyski et al. 2018	2015-01 to 2016-06	Phase 2

Immunosuppressive therapy

• Methotrexate (MTX) 15 mg/m² IV once on day +1, then 10 mg/m² IV once per day on days +3, +6, +11
• Tacrolimus (Prograf) 0.03 mg/kg/day IV from day -3 onwards
• Tocilizumab (Actemra) 8 mg/kg (maximum dose of 800 mg) IV once on day -1, approximately 24 hours before HSCT infusion

One course

Dose and schedule modifications

• Tacrolimus adjusted to maintain tacrolimus levels between 5 to 15 ng/mL

References

1. Drobyski WR, Szabo A, Zhu F, Keever-Taylor C, Hebert KM, Dunn R, Yim S, Johnson B, D'Souza A, Eapen M, Fenske TS, Hari P, Hamadani M, Horowitz MM, Rizzo JD, Saber W, Shah N, Shaw B, Pasquini M. Tocilizumab, tacrolimus and methotrexate for the prevention of acute graft-versus-host disease: low incidence of lower gastrointestinal tract disease. Haematologica. 2018 Apr;103(4):717-727. Epub 2018 Jan 19. link to original article linkt o PMC article contains dosing details in manuscript PubMed

Methotrexate, Tacrolimus, Vorinostat

Regimen variant #1, IV tacrolimus

Study	Dates of enrollment	Evidence
Choi et al. 2017 (UMCC 2012.047)	2013-06-01 to 2016-07-31	Phase 2

Immunosuppressive therapy

• Methotrexate (MTX) 5 mg/m² IV once per day on days +1, +3, +6, +11
• Tacrolimus (Prograf) 0.03 mg/kg/day IV, starting on day -3, then in absence of GVHD, tapering begins on day +100 and completes on day +180
  • Goal trough level of 8 to 12 ng/mL
• Vorinostat (Zolinza) 100 mg PO twice per day on days -10 to +100

Regimen variant #2, PO tacrolimus

Study	Dates of enrollment	Evidence
Choi et al. 2017 (UMCC 2012.047)	2013-06-01 to 2016-07-31	Phase 2

Immunosuppressive therapy

• Methotrexate (MTX) 5 mg/m² IV once per day on days +1, +3, +6, +11
• Tacrolimus (Prograf) 0.045 mg/kg/day PO, starting on day -3, then in absence of GVHD, tapering begins on day +100 and completes on day +180
  • Goal trough level of 8 to 12 ng/mL
• Vorinostat (Zolinza) 100 mg PO twice per day on days -10 to +100

References

1. UMCC 2012.047: Choi SW, Braun T, Henig I, Gatza E, Magenau J, Parkin B, Pawarode A, Riwes M, Yanik G, Dinarello CA, Reddy P. Vorinostat plus tacrolimus/methotrexate to prevent GVHD after myeloablative conditioning, unrelated donor HCT. Blood. 2017 Oct 12;130(15):1760-1767. Epub 2017 Aug 7. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01790568

Sitagliptin, Sirolimus, Tacrolimus

Regimen

Study	Dates of enrollment	Evidence
Farag et al. 2021 (IUSCC-0522)	2016-2018	Phase 2

Immunosuppressive therapy

• Sitagliptin (Januvia)
• Sirolimus (Rapamune)
• Tacrolimus (Prograf)

References

1. IUSCC-0522: Farag SS, Abu Zaid M, Schwartz JE, Thakrar TC, Blakley AJ, Abonour R, Robertson MJ, Broxmeyer HE, Zhang S. Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease. N Engl J Med. 2021 Jan 7;384(1):11-19. link to original article link to PMC article PubMed NCT02683525

Treatment, aGVHD, all lines of therapy

Ruxolitinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Jagasia et al. 2020 (REACH1)	2016-2018	Phase 2 (RT)
Zeiser et al. 2020 (REACH2)	2017-2019	Phase 3 (E-switch-ooc)	Investigator's choice	Superior ORR at day 28 (primary endpoint)

Immunosuppressive therapy

• Ruxolitinib (Jakafi) 10 mg PO twice per day

Continued for at least 56 days, tapered thereafter

References

1. REACH2: Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, Szer J, Wagner EM, Zuckerman T, Mahuzier B, Xu J, Wilke C, Gandhi KK, Socié G; REACH2 Trial Group. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med. 2020 May 7;382(19):1800-1810. Epub 2020 Apr 22. link to original article PubMed NCT02913261
2. REACH1: Jagasia M, Perales MA, Schroeder MA, Ali H, Shah NN, Chen YB, Fazal S, Dawkins FW, Arbushites MC, Tian C, Connelly-Smith L, Howell MD, Khoury HJ. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood. 2020 May 14;135(20):1739-1749. link to original article link to PMC article PubMed NCT02953678

Treatment, cGVHD, all lines of therapy

Belumosudil monotherapy

Regimen

Study	Dates of enrollment	Evidence
Cutler et al. 2021 (ROCKstar)	2018-10 to 2019-08	Phase 2 (RT)

Immunosuppressive therapy

• Belumosudil (Rezurock)

References

1. ROCKstar: Cutler C, Lee SJ, Arai S, Rotta M, Zoghi B, Lazaryan A, Ramakrishnan A, DeFilipp Z, Salhotra A, Chai-Ho W, Mehta R, Wang T, Arora M, Pusic I, Saad A, Shah NN, Abhyankar S, Bachier C, Galvin J, Im A, Langston A, Liesveld J, Juckett M, Logan A, Schachter L, Alavi A, Howard D, Waksal HW, Ryan J, Eiznhamer D, Aggarwal SK, Ieyoub J, Schueller O, Green L, Yang Z, Krenz H, Jagasia M, Blazar BR, Pavletic S. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study. Blood. 2021 Dec 2;138(22):2278-2289. Erratum in: Blood. 2022 Mar 17;139(11):1772. link to original article link to PMC article PubMed NCT03640481

Cyclosporine & Prednisone

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Arora et al. 2001	Randomized (C)	Cyclosporine, Prednisone, Thalidomide	Did not meet endpoint

Immunosuppressive therapy

• Cyclosporine
• Prednisone (Sterapred)

References

1. Arora M, Wagner JE, Davies SM, Blazar BR, Defor T, Enright H, Miller WJ, Weisdorf DF. Randomized clinical trial of thalidomide, cyclosporine, and prednisone versus cyclosporine and prednisone as initial therapy for chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2001;7(5):265-73. link to original article PubMed

Cyclosporine, Corticosteroids, Rituximab

Regimen

Study	Dates of enrollment	Evidence	Efficacy
Malard et al. 2017 (R-GVHD)	2008-2012	Phase 2	ORR at 12 mo: 83%

Immunosuppressive therapy

• Cyclosporine 6 mg/kg PO twice per day
  • Or, continued at the dose at time of study entry
  • Goal level 200 to 400 ng/mL
• Corticosteroids equivalent to 1 mg/kg/day of Prednisone (Sterapred)
• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1, 8, 15, 22

Rituximab given as a 4-week course, repeated one month later if PR or better. Corticosteroids and CsA tapered per standard of care.

References

1. R-GVHD: Malard F, Labopin M, Yakoub-Agha I, Chantepie S, Guillaume T, Blaise D, Tabrizi R, Magro L, Vanhove B, Blancho G, Moreau P, Gaugler B, Chevallier P, Mohty M. Rituximab-based first-line treatment of cGVHD after allogeneic SCT: results of a phase 2 study. Blood. 2017 Nov 16;130(20):2186-2195. Epub 2017 Sep 1. link to original article contains dosing details in manuscript PubMed NCT01135641

Cyclosporine, Sirolimus, Prednisone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Carpenter et al. 2018 (BMT CTN 0801)	NR	Phase 2/3 (C)	Sirolimus & Prednisone	Did not meet primary endpoint of CR at 2 years

Immunosuppressive therapy

• Cyclosporine
• Sirolimus (Rapamune)
• Prednisone (Sterapred)

References

1. BMT CTN 0801: Carpenter PA, Logan BR, Lee SJ, Weisdorf DJ, Johnston L, Costa LJ, Kitko CL, Bolaños-Meade J, Sarantopoulos S, Alousi AM, Abhyankar S, Waller EK, Mendizabal A, Zhu J, O'Brien KA, Lazaryan A, Wu J, Nemecek ER, Pavletic SZ, Cutler CS, Horowitz MM, Arora M; BMT CTN. A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/ sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801. Haematologica. 2018 Nov;103(11):1915-1924. Epub 2018 Jun 28. link to original article link to PMC article PubMed NCT01106833

Ibrutinib monotherapy

Regimen variant #1, adult dosing

FDA-recommended dose

Study	Dates of enrollment	Evidence	Efficacy
Miklos et al. 2017 (PCYC-1129-CA)	2014-07-14 to NR	Phase 1b/2 (RT)	Best ORR: 67%

Immunosuppressive therapy

• Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28

28-day cycles

Regimen variant #2, pediatric dosing

FDA-recommended dose

Study	Dates of enrollment	Evidence
Carpenter et al. 2022 (iMAGINE)	NR	Phase 1/2 (RT)

Immunosuppressive therapy

• Ibrutinib (Imbruvica) 240 mg/m² PO once per day on days 1 to 28

28-day cycles

References

1. PCYC-1129-CA: Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, Flowers ME, Logan AC, Nakamura R, Blazar BR, Li Y, Chang S, Lal I, Dubovsky J, James DF, Styles L, Jaglowski S. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017 Nov 23;130(21):2243-2250. Epub 2017 Sep 18. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02195869
2. iMAGINE: Carpenter PA, Kang HJ, Yoo KH, Zecca M, Cho B, Lucchini G, Nemecek ER, Schultz KR, Stepensky P, Chaudhury S, Oshrine B, Khaw SL, Harris AC, Verna M, Zubarovskaya L, Lee Y, Wahlstrom J, Styles L, Shaw PJ, Dalle JH. Ibrutinib Treatment of Pediatric Chronic Graft-versus-Host Disease: Primary Results from the Phase 1/2 iMAGINE Study. Transplant Cell Ther. 2022 Nov;28(11):771.e1-771.e10. Epub 2022 Aug 28. link to original article contains dosing details in abstract PubMed NCT03790332

Prednisone monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Miklos et al. 2023 (iNTEGRATE)	NR	Phase 3 (C)	Ibrutinib & Prednisone	Did not meet primary endpoint of RR at 48 weeks

Immunosuppressive therapy

• Prednisone (Sterapred) 1 mg/kg PO once per day, adjusted as necessary

Continued indefinitely, with a suggested 6-month taper (see supplement for details)

References

1. iNTEGRATE: Miklos DB, Abu Zaid M, Cooney JP, Albring JC, Flowers M, Skarbnik AP, Yakoub-Agha I, Ko BS, Bruno B, Waller EK, Yared J, Sohn SK, Bulabois CE, Teshima T, Jacobsohn D, Greinix H, Mokatrin A, Lee Y, Wahlstrom JT, Styles L, Socie G. Ibrutinib for First-Line Treatment of Chronic Graft-Versus-Host Disease: Results From the Randomized Phase III iNTEGRATE Study. J Clin Oncol. 2023 Apr 1;41(10):1876-1887. Epub 2023 Jan 6. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02959944

Ruxolitinib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Zeiser et al. 2021 (REACH3)	2017-2019	Phase 3 (E-RT-switch-ooc)	Best available therapy	Superior ORR at week 24 (primary endpoint)

Immunosuppressive therapy

• Ruxolitinib (Jakafi) 10 mg PO twice per day

28-day cycle for at least 6 cycles

References

1. REACH3: Zeiser R, Polverelli N, Ram R, Hashmi SK, Chakraverty R, Middeke JM, Musso M, Giebel S, Uzay A, Langmuir P, Hollaender N, Gowda M, Stefanelli T, Lee SJ, Teshima T, Locatelli F; REACH3 Investigators. Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease. N Engl J Med. 2021 Jul 15;385(3):228-238. link to original article contains dosing details in manuscript PubMed NCT03112603

Sirolimus, Tacrolimus, Prednisone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Carpenter et al. 2018 (BMT CTN 0801)	NR	Phase 2/3 (C)	Sirolimus & Prednisone	Did not meet primary endpoint of CR at 2 years

Immunosuppressive therapy

• Sirolimus (Rapamune)
• Tacrolimus (Prograf)
• Prednisone (Sterapred)

References

1. BMT CTN 0801: Carpenter PA, Logan BR, Lee SJ, Weisdorf DJ, Johnston L, Costa LJ, Kitko CL, Bolaños-Meade J, Sarantopoulos S, Alousi AM, Abhyankar S, Waller EK, Mendizabal A, Zhu J, O'Brien KA, Lazaryan A, Wu J, Nemecek ER, Pavletic SZ, Cutler CS, Horowitz MM, Arora M; BMT CTN. A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/ sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801. Haematologica. 2018 Nov;103(11):1915-1924. Epub 2018 Jun 28. link to original article link to PMC article PubMed NCT01106833

Response criteria

2005 NIH cGVHD Consensus Panel

References

1. Pavletic SZ, Martin P, Lee SJ, Mitchell S, Jacobsohn D, Cowen EW, Turner ML, Akpek G, Gilman A, McDonald G, Schubert M, Berger A, Bross P, Chien JW, Couriel D, Dunn JP, Fall-Dickson J, Farrell A, Flowers ME, Greinix H, Hirschfeld S, Gerber L, Kim S, Knobler R, Lachenbruch PA, Miller FW, Mittleman B, Papadopoulos E, Parsons SK, Przepiorka D, Robinson M, Ward M, Reeve B, Rider LG, Shulman H, Schultz KR, Weisdorf D, Vogelsang GB; Response Criteria Working Group. Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant. 2006 Mar;12(3):252-66. link to original article PubMed

2014 NIH Response Criteria

References

1. Lee SJ, Wolff D, Kitko C, Koreth J, Inamoto Y, Jagasia M, Pidala J, Olivieri A, Martin PJ, Przepiorka D, Pusic I, Dignan F, Mitchell SA, Lawitschka A, Jacobsohn D, Hall AM, Flowers ME, Schultz KR, Vogelsang G, Pavletic S. Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report. Biol Blood Marrow Transplant. 2015 Jun;21(6):984-99. Epub 2015 Mar 19. link to PMC article

Scoring

Glucksberg acute graft versus host (GVHD) scores

Skin

• Stage 0: No rash
• Stage 1: Maculopapular rash <25% of body surface area
• Stage 2: Maculopapular rash on 25-50% of body surface area
• Stage 3: Generalized erythroderma
• Stage 4: Generalized erythroderma with bullous formation and desquamation

Liver

• Stage 0: Bilirubin <2 mg/dL
• Stage 1: Bilirubin 2-3 mg/dL
• Stage 2: Bilirubin 3.01-6 mg/dL
• Stage 3: Bilirubin 6.01-15 mg/dL
• Stage 4: Bilirubin >15 mg/dL

GI

• Stage 0: No diarrhea, or diarrhea less than 500 mL/day
• Stage 1: Diarrhea 500-999 mL/day
• Stage 2: Diarrhea 1000-1499 mL/day
• Stage 3: Diarrhea >1500 mL/day
• Stage 4: Severe abdominal pain, with or without ileus

Glucksberg grade

Overall grade	I	II	III	IV
Skin	1-2	1-3	2-3	2-4
GI	0	1	2-3	2-4
Liver	0	1	2-4	2-4
Karnofsky performance scale	90-100%	70-80%	50-60%	30-40%

IBMTR severity index

The severity is the highest level which the patient reaches based on separate skin, liver, and GI staging.

Overall grade	A	B	C	D
Skin	1	2	3	4
GI	0	1-2	3	4
Liver	0	1-2	3	4

Chronic GVHD

Localized

• Localized skin and/or liver dysfunction due to chronic GVHD

Extensive

• Generalized skin involvement or localized skin and/or liver dysfunction due to chronic GVHD plus at least one of the following:
  • Liver biopsy showing cirrhosis, chronic aggressive hepatitis, bridging necrosis
  • Eye involvement, defined as Schirmer's test with less than 5 mm wetting
  • Involvement of oral mucosa on lip biopsy or minor salivary glands
  • Other organ involvement
• Overall severity categories: mild/moderate/severe

References

1. Thomas E, Storb R, Clift RA, Fefer A, Johnson FL, Neiman PE, Lerner KG, Glucksberg H, Buckner CD. Bone-marrow transplantation (first of two parts). N Engl J Med. 1975 Apr 17;292(16):832-43 link to original article PubMed
2. Thomas ED, Storb R, Clift RA, Fefer A, Johnson L, Neiman PE, Lerner KG, Glucksberg H, Buckner CD. Bone-marrow transplantation (second of two parts). N Engl J Med. 1975 Apr 24;292(17):895-902 link to original article (contains staging scale) PubMed
3. Rowlings PA, Przepiorka D, Klein JP, Gale RP, Passweg JR, Henslee-Downey PJ, Cahn JY, Calderwood S, Gratwohl A, Socié G, Abecasis MM, Sobocinski KA, Zhang MJ, Horowitz MM. IBMTR Severity Index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. Br J Haematol. 1997 Jun;97(4):855-64. link to original article PubMed